Rationale: Medication nonadherence is the highest determinant of relapse in schizophrenia. Interventions that help patients remain on medication for extended periods could substantially improve clinical outcomes. Significance: The revised R01 renewal application will advance the development of an implantable long-term risperidone delivery system to improve medication adherence in schizophrenia. Achieving this goal could improve the health and quality of life for millions of people with schizophrenia and their families. Progress: We completed both Aims during the previous period by performing in vitro-in vivo correlation (IVIVC) modeling for sterile, biodegradable implants. In the previous 2-year funding period, we developed a long-term risperidone delivery system using the biodegradable polymer poly-lactide-co-glycolide (PLGA). First, we determined in vitro risperidone release from multiple types of implants by varying lactide to glycolide ratios. We then determined in vivo serum risperidone concentration from a New Hypothesis: We propose that the benefits of long term delivery systems extend beyond a safety net against relapse. Preliminary data suggest that steady state infusion of antipsychotic medication from implants could provide consistent modulation of dopaminergic tone intermittent oral administration allowing the brain to remodel in a stable therapeutic environment. Studies in this application would test this hypothesis using animal models of antipsychotic efficacy and side effects. Proposed Studies: The current application would determine how constant risperidone infusion from implants affects behavioral (Aim 1), biochemical (Aim 2) and molecular (Aim 3) measures of efficacy and side effects comparison to three times daily oral administration in rodents.